| Title: | Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation |
| Journal: | eLife |
| Published: | 25 Jan 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35074047/ |
| DOI: | https://doi.org/10.7554/elife.72452 |
| Citations: | 26 (21 in last 2 years) as of 8 Aug 2024 |
Publication 12590
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Abstract
Background: Some individuals living with obesity may be relatively metabolically healthy, whilst others suffer from multiple conditions that may be linked to adverse metabolic effects or other factors. The extent to which the adverse metabolic component of obesity contributes to disease compared to the non-metabolic components is often uncertain. We aimed to use Mendelian randomisation (MR) and specific genetic variants to separately test the causal roles of higher adiposity with and without its adverse metabolic effects on diseases.</p>
Methods: We selected 37 chronic diseases associated with obesity and genetic variants associated with different aspects of excess weight. These genetic variants included those associated with metabolically 'favourable adiposity' (FA) and 'unfavourable adiposity' (UFA) that are both associated with higher adiposity but with opposite effects on metabolic risk. We used these variants and two sample MR to test the effects on the chronic diseases.</p>
Results: MR identified two sets of diseases. First, 11 conditions where the metabolic effect of higher adiposity is the likely primary cause of the disease. Here, MR with the FA and UFA genetics showed opposing effects on risk of disease: coronary artery disease, peripheral artery disease, hypertension, stroke, type 2 diabetes, polycystic ovary syndrome, heart failure, atrial fibrillation, chronic kidney disease, renal cancer, and gout. Second, 9 conditions where the non-metabolic effects of excess weight (e.g. mechanical effect) are likely a cause. Here, MR with the FA genetics, despite leading to lower metabolic risk, and MR with the UFA genetics, both indicated higher disease risk: osteoarthritis, rheumatoid arthritis, osteoporosis, gastro-oesophageal reflux disease, gallstones, adult-onset asthma, psoriasis, deep vein thrombosis, and venous thromboembolism.</p>
Conclusions: Our results assist in understanding the consequences of higher adiposity uncoupled from its adverse metabolic effects, including the risks to individuals with high body mass index who may be relatively metabolically healthy.</p>
Funding: Diabetes UK, UK Medical Research Council, World Cancer Research Fund, National Cancer Institute.</p>
13 Keywords
- Adiposity
- Adult
- Aged
- Aged, 80 and over
- Body Mass Index
- Cardiometabolic Risk Factors
- Female
- Genome-Wide Association Study
- Humans
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Obesity
25 Authors
- Susan Martin
- Jessica Tyrrell
- E Louise Thomas
- Matthew J Bown
- Andrew R Wood
- Robin N Beaumont
- Lam C Tsoi
- Philip E Stuart
- James T Elder
- Philip Law
- Richard Houlston
- Christopher Kabrhel
- Nikos Papadimitriou
- Marc J Gunter
- Caroline J Bull
- Joshua A Bell
- Emma E Vincent
- Naveed Sattar
- Malcolm G Dunlop
- Ian PM Tomlinson
- Sara Lindström
- INVENT consortium
- Jimmy D Bell
- Timothy M Frayling
- Hanieh Yaghootkar
Enabling scientific discoveries that improve human health